Synergistic Induction of Adaptive Antitumor Immunity by Codelivery of Antigen with α-Galactosylceramide on Exosomes

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-07, Vol.73 (13), p.3865-3876
• Main Authors: GEHRMANN, Ulf, HILTBRUNNER, Stefanie, GEORGOUDAKI, Anna-Maria, KARLSSON, Mikael C, NÄSLUND, Tanja I, GABRIELSSON, Susanne
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Adjuvants, Immunologic - administration & dosage; Amino Acid Sequence; Animals; Antigens, CD1d - metabolism; Antigens, Neoplasm - administration & dosage; Antigens, Neoplasm - immunology; Antineoplastic agents; B-Lymphocytes - immunology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Clonal Anergy; Dendritic Cells - secretion; Exosomes - immunology; Female; Galactosylceramides - administration & dosage; Immunotherapy, Adoptive; Lymphocyte Activation; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Natural Killer T-Cells - immunology; Neoplasm Transplantation; Ovalbumin - immunology; Peptide Fragments - immunology; Pharmacology. Drug treatments; Tumor Burden - immunology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-3918

Exosomes and the invariant NKT (iNKT) immune cell ligand α-galactosylceramide (αGC) may offer novel tools for cancer immunotherapy. In this study, we investigated whether exosomes loaded with αGC can activate iNKT cells and potentiate a cancer-specific adaptive immune response. αGC loaded exosomes readily activated iNKT cells both in vitro and in vivo. Exosomes loaded with αGC plus the model antigen ovalbumin (OVA) induced potent NK and γδ T-cell innate immune responses, and they also synergistically amplified T- and B-cell responses that were OVA specific. In contrast to soluble αGC, which anergizes iNKT cells, we found that αGC/OVA-loaded exosomes did not induce iNKT cell anergy but were more potent than soluble αGC + OVA in inducing adaptive immune responses. In an OVA-expressing mouse model of melanoma, treatment of tumor-bearing mice with αGC/OVA-loaded exosomes decreased tumor growth, increased antigen-specific CD8(+) T-cell tumor infiltration, and increased median survival, relative to control mice immunized with soluble αGC + OVA alone. Notably, an additional injection of αGC/OVA-loaded exosomes further augmented the treatment effects. Our findings show that exosomes loaded with protein antigen and αGC will activate adaptive immunity in the absence of triggering iNKT-cell anergy, supporting their application in the design of a broad variety of cancer immunotherapy trials.